Conservation of Immunoglobulin Variable and Joining Region Structure and the Design of Universal Anti-Immunoglobulin Antibodies Reactive with Antigen-Binding T Cell Receptors

Marchalonis, John J.; Schluter, Samuel F.; Hubbard, Roger A.; Diamanduros, Andrew; Barker, Winona C.; Pumphrey, R. S. H.

doi:10.3109/08830188809051191

Cited by 16 publications

(5 citation statements)

References 63 publications

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“…These evolutionary data buttress identification ofrearranging TCRs as types ofimmunoglobulin based upon sequence (27) and predicted conformations (28,29) and strengthen our conclusion, based upon antigenic and conformational analyses of Jp peptides, that TCR P chains resemble immunoglobulin light chains (9). Dendograms based upon comparisons of mammalian immunoglobulin and TCR Vregion sequences suggest that immunoglobulin heavy and light chains might have diverged prior to the distinction between T and B cells (30). Our present data suggest that the shark light chain has properties very similar to those that would be expected for the form ancestral to immunoglobulin light chains and TCRs.…”

Section: Resultssupporting

confidence: 73%

Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions.

Schluter

Hohman

Edmundson

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Sharks are living fossils that are indistinguishable morphologically from their Devonian ancestors of =400 million years ago. If parallel conservatism characterizes their biochemical evolution, characterization of their immunoglobulin chains could provide information regarding the primordial features of these essential defense molecules. Shark immunoglobulins are polydisperse like those of mammals, but these species lack homogeneous myeloma proteins. This heterogeneity has precluded direct determination of the sequence of elasmobranch light-chain proteins. We have sequenced four cDNA clones that contain the constant-region sequence as well as varying degrees of variable-or joining-region segments. The sandbar shark (Carcharhinus plumbeus) has at least four distinct light-chain constant regions, and these can be considered homologs of mammalian A chains. Approximately 40% identity was found in comparison from sharks to mammals. Certain stretches of sequence were remarkably conserved, whereas others varied in a manner consistent with accepted concepts of speciation. One hexapeptide (Ala-Thr-LeuVal-Cys-Leu) occurred in A constant regions of all vertebrate species. There was a universal conservation of certain cysteines, phenylalanines, tryptophans, and glycines and strong identities in the block of residues from Ser-176 to Comparison of the shark sequence with that of the characterized human A myeloma protein Mcg indicates a strong conservation of three-dimensional structure in this light-chain domain representing species whose ancestors diverged early in vertebrate evolution. The shark light-chain sequence contains primordial features shared by mammalian K and A chains and by T-cell receptor 13 chains.Although it has been known for many years that primitive vertebrates such as sharks (1, 2) express circulating antibodies resembling human immune macroglobulins, IgM class, in polypeptide chain structure and charge dispersity, the lack of homogeneous myeloma proteins in these species has precluded the determination of complete sequences of these molecules. Since elasmobranchs are living fossils whose ancestors diverged from those of mammals more than 400 million years ago, knowledge of the sequence of shark immunoglobulin is essential for our understanding of the evolution of the immunoglobulin system. The rearranging immunoglobulin system [in which we include the T-cell receptor (TCR) genes] is thus far unique because at least three separate genetic elements specifying variable (V) regions, joining (J) segments, and constant (C) regions are required for the system to be operational (3). It has been possible to investigate shark heavy-chain genes based initially upon the ability of the V regions to hybridize with probes directed against mammalian VH sequences (4). However, comparable probes have not been used successfully to isolate genes specifying light polypeptide chains of shark immunoglobulins. To circumvent this difficulty, we prepared cDNA from splenic mRNA of the sandbar shark (Carcharhinus plumbeus)...

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Section: Resultssupporting

confidence: 73%

Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions.

Schluter

Hohman

Edmundson

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…Based upon the homology between T-cell receptors and immunoglobulin light chains, we (17,20) and other investigators (4144) have predicted the 3-dimensional structures. of the T-cell receptors.…”

Section: Molecular Modeling and Epitope Mapping Of Tcr Alpmentioning

confidence: 96%

“…We will use the data available on the structure of immunoglobulins and on the construction of synthetic and recombinant idiotypes (3,4,3&40) in conjunction with recent modeling of Tcrs (17,20,(41)(42)(43)(44) to provide a framework for interpreting the antigenic and functional structures of Ig/Tcr V and C domains. The levels and isotype expression (IgM or IgG) of autoantibodies to Tcr peptide-defined regions are dependent upon the following conditions: aging, autoimmune disease, allograft transplantation, pregnancy, and retroviral in-fection.…”

Section: Autoantibodies To Immunoglobulins Andmentioning

confidence: 99%

“…The Fr4 sequence specified by Jp segment shows strong homology to K and A light chains and Tcr a and p chains. These segments are responsible for some of the broad cross-reactions demon-strated between the immunoglobulin and Tcr protein (16,17,23). The positively charged residues (lysine or arginine) in the sequence FGXGT (K or R) LV have been found to be essential for the cross-reaction between light chains and Tcrs (16).…”

Section: N K V F P P E V a V F E P S A E I S H T O K A T L V C L A T mentioning

confidence: 99%

“…By analogy with properties of anti-idiotypic sera against light chains of rheumatoid factors (38), we would con- (51). The set of peptides (a10, 11; pl0, 11; Mcg10) containing the Fr4 segment that is encoded by the joining region gene of Tcrs and light chains is of interest because the FGXGT+L motif is highly conserved in Tcrs and light chains of species widely spread in vertebrate evolution (13, 15,17). Usually, there is little detectable natural reactivity directed against this region of the molecule.…”

Section: N K V F P P E V a V F E P S A E I S H T O K A T L V C L A T mentioning

confidence: 99%

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Synthetic Autoantigens of Immunoglobulins and T-Cell Receptors: Their Recognition in Aging, Infection, and Autoimmunity

Marchalonis

Schluter

Wang

et al. 1994

Experimental Biology and Medicine

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Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the alpha/beta T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are "constitutive" markers inasmuch as all individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the "private idiotypes" defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcr alpha chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic V beta CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including examples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor structural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synthetic and recombinant reagents for modulation of autoimmune and infectious diseases.

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Antibodies to synthetic peptides corresponding to variable-region first-framework segments of T cell receptors

et al. 1989

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Recent studies at the gene level have shown that T cells express rearranged genes for four types of T cell receptors that are strongly homologous to classical immunoglobulins in the joining region and in the framework 1 (Fr1) and 3 segments of the variable region. Based upon the homologies in gene sequence, it follows that the gene products would show similarities in amino acid sequence and in the folding of the proteins so that cross-reactivities in antigenic determinants would be expected between variable regions of the T cell receptors and classical immunoglobulins. We have synthesized peptides corresponding to predicted protein sequences of the Fr1 residues of T cell receptor alpha, beta- and gamma-chains and have produced antibodies in rabbits against these synthetic peptides. Use of antisera and affinity-purified antipeptide antibodies indicated that high-titer antibodies could be raised that were specific for individual Fr1 peptides. Cross-reactions among Fr1 peptides of T cell receptors and immunoglobulin light chains were observed. In addition, some rabbit antisera raised against classical polyclonal immunoglobulins or affinity-purified immunoglobulin-like T cell receptors were found to exhibit binding activity against Fr1 peptides of T cell receptor beta- and gamma-chains. The sequence homology, although real among the Fr1 of T cell receptors and immunoglobulin light chains, is moderate and the antigenic cross-reaction must reflect the configuration and types of amino acids present. The development of antipeptide antibodies holds promise for the characterization of T cell receptors of various T cell sources and also offers a new means for the identification of molecules related to rearranging immunoglobulins.

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Conservation of Immunoglobulin Variable and Joining Region Structure and the Design of Universal Anti-Immunoglobulin Antibodies Reactive with Antigen-Binding T Cell Receptors

Cited by 16 publications

References 63 publications

Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions.

Evolution of immunoglobulin light chains: cDNA clones specifying sandbar shark constant regions.

Synthetic Autoantigens of Immunoglobulins and T-Cell Receptors: Their Recognition in Aging, Infection, and Autoimmunity

Antibodies to synthetic peptides corresponding to variable-region first-framework segments of T cell receptors

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